There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching several interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes; 2)Ascertainment of the consequences of over- or under-expressing candidate genes identified in human studies; 3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation; 4) Studying influences of interactions between variants at different genomic loci; 5)Elucidating haplotype-specific levels of expression differences in vivo, 6) allowing us to monitor synaptic connectivities and their modulation by drug administration and alterations in haplotypes in cell adhesion and other important brain molecules and 7) allowing derisking or assessment of the levels of risk likely to accompany potential pharmacotherapeutics that target the gene whose expression is modified. Interest mechanisms of reward, reinforcement and learning have led to continuing focus on these systems during this year, as we have established much of the groundwork for identification of wiring differences in brain. In continuing studies of knockouts of candidate genes that are interesting because they encode drug targets and/or are expressed in circuits of interest, we have reported novel data concerning the differential influences of these knockouts on a) adaptive responses to cocaine b) stress engendered by social defect (mu/OPRM1 knockouts)c) antidepressants and analgesics (OPRM1 knockouts) d) substance-induced dopamine release (mu/OPRM1 knockouts) e) brain circuitry (DAT/SLC6A3 knockouts) and f) pain responses (DAT/SLC6A4, SERT/SLC6A4 and mu/OPRM1 knockouts). We have moved forward with studies of the influences of cell adhesion gene alterations by studies of mice with altered expression of the four genes for which our human genome wide association datasests provide the most consistent replication. We have submitted data that mice with homozygous or heterozygous deletion of the two genes for which we have the strongest evidence in humans, CDH13,PTPRD and CSMD1, reduce preference for environments paired with 10 mg/kg cocaine doses. These results display specificity, since cocaine retains locomotor stimulation and since these knockout mice can perform at normal (or supranormal) levels in Morris water maze and other comparison behaviors. Initial data supports the possibility that the magnitude of extinction and reinstatement are also reduced in CDH13 knockouts. These animals thus provide one of the best mouse confirmations of a genome wide association result from a complex, polygenic human locus. Interestingly, these mice also display greater reward from 5 mg/kg cocaine doses. These data are convergent with results from human laboratory studies of individual differences in cocaine responses, and individual differences in responses to initial alcohol doses. We have begun to seek neural and neurochemical correlates of these behavioral changes. In initial studies of CDH13 knockout mice, we have identified alterations in levels of cerebral cortical dopamine and in densities of prefrontal cortical dopaminergic fibers. If confirmed, these results would provide a basis for the selective behavioral results that accompany altered expression of CDH13 in mice and in humans.